1,721,061 research outputs found
GJB2 Gene Mutations in Syndromic Skin Diseases with Sensorineural Hearing Loss.
No full textThe GJB2 gene is located on chromosome 13q12 and it encodes the connexin 26, a transmembrane protein involved in cell-cell attachment of almost all tissues. GJB2 mutations cause autosomal recessive (DFNB1) and sometimes dominant (DFNA3) non-syndromic sensorineural hearing loss. Moreover, it has been demonstrated that connexins are involved in regulation of growth and differentiation of epidermis and, in fact, GJB2 mutations have also been identified in syndromic disorders with hearing loss associated with various skin disease phenotypes. GJB2 mutations associated with skin disease are, in general, transmitted with a dominant inheritance pattern. Nonsyndromic deafness is caused prevalently by a loss-of-function, while literature evidences suggest for syndromic deafness a mechanism based on gain-of-function. The spectrum of skin manifestations associated with some mutations seems to have a very high phenotypic variability. Why some mutations can lead to widely varying cutaneous manifestations is poorly understood and in particular, the reason why the skin disease-deafness phenotypes differ from each other thus remains unclear. This review provides an overview of recent findings concerning pathogenesis of syndromic deafness imputable to GJB2 mutations with an emphasis on relevant clinical genotype-phenotype correlations. After describing connexin 26 fundamental characteristics, the most relevant and recent information about its known mutations involved in the syndromic forms causing hearing loss and skin problems are summarized. The possible effects of the mutations on channel expression and function are discussed
Modulation of the K+ channels encoded by the Human ether-a-gogo-related gene 1 (hERG1) by nitric oxide
No full textThe inhibition of nitric oxide synthase by N-nitro-L-arginine methyl ester (0.03-3 mM) dose-dependently reduced nitric oxide (NO(*)) levels and enhanced the outward currents carried by human ether-a-gogo-related gene-1 (hERG1) K(+) channels expressed in Xenopus laevis oocytes, whereas the increase in NO(*) levels achieved by exposure to L-arginine (0.03-10 mM) inhibited these currents. Furthermore, four NO(*) donors belonging to such different chemical classes as sodium nitroprusside (1-1000 microM), 3-morpholino-sydnonimine (100-1000 microM), (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1- ium-1, 2-diolate (NOC-18; 1-300 microM), and S-nitroso N-acetylpenicillamine (1-300 microM) dose-dependently inhibited hERG1 outward K(+) currents. By contrast, the NO(*) donor NOC-18 (0.3 mM) did not affect other cloned K(+) channels such as rat neuroblastoma-glioma K(+) channel 2, rat delayed rectifier K(+) channel 1, bovine ether-a-gogo gene, rat ether-a-gogo-related gene-2, and rat ether-a-gogo-related gene-3. The inhibitory effect of NO(*) donors on hERG1 K(+) channels was prevented by the NO(*) scavengers 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide and hemoglobin. The membrane permeable analog of cGMP, 8-bromo-cGMP (1 mM), failed to reproduce the inhibitory action of NO(*) donors on hERG1 outward currents; furthermore, the specific inhibitor of the NO(*)-dependent guanylyl cyclase, 1H-[1,2,4]oxadiazolo[4, 3-a]quinoxalin-1-one (50 microM), neither interfered with outward hERG1 K(+) currents nor prevented their inhibition by 0.3 mM NOC-18. Both L-arginine (10 mM) and NOC-18 (0.3 mM) counteracted the stimulatory effect on hERG1 outward currents induced by the radical oxygen species-generating system FeSO(4) (25 microM)/ascorbic acid (50 microM; Fe/Asc). Finally, L-arginine (10 mM) and NOC-18 (0.3 mM) inhibited both basal and Fe/Asc (0.1 mM/0.2 mM)-stimulated lipid peroxidation in X. laevis oocytes. Collectively, the present results suggest that NO(*), both endogenously produced and pharmacologically delivered, may exert in a cGMP-independent way an inhibitory effect on hERG1 outward K(+) currents via an interaction with radical oxygen species either generated under resting conditions or triggered by Fe/Asc
Prolonged changes in hepatic mitochondrial activity and insulin sensitivity by high fructose intake in adolescent rats
Full text linkPersistence of damage induced by unhealthy diets during youth has been little addressed. Therefore, we investigated the impact of a short‐term fructose‐rich diet on liver metabolic activity in adolescent rats and the putative persistence of alterations after removing fructose from the diet. Adolescent rats were fed a fructose‐rich diet for three weeks and then switched to a control diet for further three weeks. Body composition and energy balance were not affected by fructose‐rich diet, while increased body lipids and lipid gain were found after the rescue period. Switching to a control diet reversed the upregulation of plasma fructose, uric acid, lipocalin, and haptoglobin, while plasma triglycerides, alanine aminotransferase, lipopolysaccharide, and tumor necrosis factor alpha remained higher. Hepatic steatosis and ceramide were increased by fructose‐rich diet, but reversed by returning to a control diet, while altered hepatic response to insulin persisted. Liver fatty acid synthase and stearoyl‐CoA desaturase (SCD) activities were upregulated by fructose‐rich diet, and SCD activity remained higher after returning to the control diet. Fructose‐induced upregulation of complex II‐driven mitochondrial respiration, peroxisome proliferator‐activated receptor‐gamma coactivator 1 alpha, and peroxisome proliferator activated receptor α also persisted after switching to control diet. In conclusion, our results show prolonged fructose‐induced dysregulation of liver metabolic activity
INHIBITORS OF RAS FARNESYLATION REVERT THE INCREASED RESISTANCE TO OXIDATIVE STRESS IN Ki-RAS TRANSFORMED NIH 3T3 CELLS
No full textThe mechanism of stimulation of respiration in isolated hepatocytes from rats fed an energy dense diet
No full textINHIBITORS OF RAS FARNESYLATION REVERT THE INCREASED RESISTANCE TO OXIDATIVE STRESS IN Ki-RAS TRANSFORMED NIH 3T3 CELLS
No full textMorphological and functional modifications of rat liver peroxisomal subpopulations during cold exposure
No full textA report is made (during cold exposure) of: a) the morphometric-stereologic analysis both on the whole rat liver peroxisomal population, and on 2 peroxisomal subpopulations having a diameter greater than 0.5 microns, and less than 0.5 microns, called Pe (Peroxisomes) and sPe (small Peroxisomes), respectively; b) the uricase and palmitoyl-coenzyme A oxidase activity assay on 2 classes of rat liver peroxisomes, sedimenting at 10,000 g and 27,000 g and containing Pe and sPe, respectively. The peroxisomal volume and number densities increase during cold exposure, reaching a maximum (+67% and +130%, respectively, P less than 0.05) at 10 days. These modifications are accompanied by an appreciable reduction of the average peroxisome volume (from 0.27 +/- 0.05 microns 3 to 0.19 +/- 0.02 microns 3) due to a major percentage increase of sPe during cold exposure. At a qualitative level, the formation of "clusters" and a stricter association between mitochondria and peroxisomes is also observed. Cold exposure increases the oxidative capacity of the whole peroxisomal compartment; in the Pe fraction the palmitoyl-CoA oxidase and uricase specific activity ratio is constant (about 0.1), during cold exposure, but in the sPe fraction this ratio increases significantly (from 0.05 to 0.09). The results indicate that the peroxisomal population is influenced during cold exposure, with the formation of a new peroxisomal population which is on average smaller and more specialized for the beta-oxidative activity. The possible involvement of peroxisomes in thermoregulatory thermogenesis during cold exposure is also discussed
Modulation of the K(+) channels encoded by the human ether-a-gogo-related gene-1 (hERG1) by nitric oxide
Full text linkModulation of the K(+) channels encoded by the human ether-a-gogo-related gene-1 (hERG1) by nitric oxide
No full textSECRETION AND INCREASE OF INTRACELLULAR CuZn SUPEROXIDE DISMUTASE CONTENT IN HUMAN NEUROBLASTOMA SK-N-BE CELLS SUBJECTED TO OXIDATIVE STRESS
No full textCuZn superoxide dismutase (SOD) secretion was detected in media of [S-35]cysteine-labeled human neuroblastoma SK-N-BE cells precipitated with antihuman CuZn SOD antibodies. The ability of Fe2+/ascorbate oxidative stress to induce CuZn SOD in SK-N-BE cells was evaluated by Western blot analysis. The results showed that, like human hepatocarcinoma cells and human fibroblasts, SK-N-BE cells secrete CuZn SOD. In addition, the CuZn SOD concentration was higher in cells subjected to oxidative stress than in unstressed cells. The secretion of CuZn SOD and the ability of Fe2+/ascorbate to increase its protein content in SK-N-BE cells indicates that this enzyme protects the brain from damage induced by oxidative stress. (C) 1998 Elsevier Science Inc
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